Project Summary/Abstract Alzheimer?s disease (AD) affects 5.5 million Americans producing cognitive deficits and mortality. There is no treatment for AD, thus, development of interventions to slow or reverse AD symptoms is a critical area of research. Furthermore, AD is difficult to detect until substantial neurodegeneration has already occurred. This proposal investigates proteasome function both as an intervention to AD symptoms and as a tool for early stage diagnosis in peripheral tissues. A key symptom of AD is proteostatic dysfunction. Patients as well as animal models of AD have a pronounced decline in proteasome function. Using in vivo invertebrate and in vitro vertebrate models of AD, we have found that genetic and pharmacologic augmentation of proteasome delays cognitive and neurodegenerative symptoms, while reducing proteasome function accelerates AD progression. This proposal builds on the above exciting findings and is designed in response to RFA-AG-18-020, Role of Peripheral Proteostasis on Brain Aging and Alzheimer's Disease. The proposal has three goals. The first goal is to develop a mechanistic understanding of how proteasome dysfunction is linked to AD progression. We present, and test, two hypotheses to explain this interplay. The first hypothesis is that the proteasome has a key role in prevention of AD progression through degradation of ?-amyloid (A?) machinery and or its substrate (APP, BACE1, and ?-secretase activators, are all targets of proteasome degradation). If our results bear out, it would indicate that age-related declines in proteasome function result in a build-up of these proteins, which accelerates AD progression. The second hypothesis we test is if proteasome dysfunction triggered by A? inhibition drives downstream neurodegeneration rather than altering A? accumulation. Proteasome dysfunction on its own is shown to cause neurodegeneration and synaptic loss. If our findings are consistent with this, it would indicate that proteasome dysfunction caused by A? inhibition is an intermediator for AD-induced cognitive deficits and neurodegeneration. The second goal is to test if AD triggers proteasome dysfunction in peripheral tissues as a diagnostic tool for early AD screening. We have initial findings supporting this. The third goal is to test if genetic or pharmacologic proteasome augmentation is a germane target for treatment of AD-like symptoms in mice that model AD. These experiments are designed to advance us toward the long-term goal of developing novel screening tools and treatments for AD in humans. This multi-PI project, led by a new investigator, seeks to develop a mechanistic understanding of the interplay between the proteasome and AD, test the efficacy of genetic and pharmacologic proteasome manipulation as an AD intervention, and test the viability of peripheral proteasome dysfunction as an early diagnosis tool. Our innovative models, state-of-the-art methods, expert investigative team, compelling preliminary data, novel pharmacologics, new transgenic lines, and diverse biological systems increase the likelihood of successfully achieving our goals and provide potential for clinical relevance.